Restorative composition for hard tissue and dispensing apparatus therefor

ABSTRACT

A restorative composition for hard tissue, comprising a paste (A) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization initiator, and a paste (B) containing an inorganic calcium phosphate powder, a polymerizable monomer mixture and a polymerization accelerator, wherein the content of the inorganic calcium phosphate powder in each paste is 75-85% by weight, and each monomer mixture contains a monomer of the formula (1): ##STR1## and a monomer of the formula (2): ##STR2## the content of the monomer (1) accounting for 40-65% by weight of the monomer mixture as a whole. The composition can well adhere to the bone and has a sufficient water resistance. As it generates little heat upon hardening, it is less detrimental to the patient&#39;s tissues. Furthermore, the paste has an appropriate consistency, which facilitates homogeneous mixing of the paste and application of the resultant mixture to the affected part by the use of a dispensing apparatus. Thus, the restorative composition can be used not only as a bone cement but also as a filler for the defected part of the bone, a bone prosthesis or an artificial bone.

TECHNICAL FIELD

The present invention relates to a restorative composition for hardtissue, which is used as a bone cement, a bone prosthesis, an artificialbone, and the like, and to a method for dispensing the restorativecomposition for hard tissue.

BACKGROUND ART

A bone cement comprising a powder agent containing polymethylmethacrylate and benzoyl peroxide (polymerization initiator), and aliquid agent containing methyl methacrylate and a tertiary amine such asN,N-dimethyl-p-toluidine (accelerator) has been conventionally used forfixing artificial joints. This bone cement is prepared immediatelybefore fixing artificial joints during operation by mixing the powderagent and the liquid agent. The obtained mixture is applied to theaffected part by a dispenser called a cement gun and allowed to cure.Such bone cement is associated with problems in that 1 the toxicity ofmethyl methacrylate causes vasodepression in patients undergoingoperation, 2 the heat generated during polymerization could give damagesto the tissues of the patients, 3 the fixed artificial joints could getloose with time due to the failure in adhering polymethyl methacrylateto hard tissues, 4 the mixing of the powder agent and the liquid agentjust before use makes bad smell of polymethyl methacrylate fill theoperation room and gives detrimental effect 5 slow mixing of the powderagent and the liquid agent leads to initiation of curing of the mixture,thereby making the mixture unavailable as a bone cement, and 6insufficient mixing of the powder agent and the liquid agent results intoo low a strength of the cured material, so that the artificial jointscannot be firmly fixed with hard tissues.

In an attempt to improve the biocompatibility of bone cements, JapanesePatent Examined Publication No. 42384/1979 has proposed a bone cementcomprising a composition containing polymethyl methacrylate and methylmethacrylate, and bioactive glass having an apatite crystal phasesuperior in biocompatibility, and Japanese Patent Application under PCTlaid-open under Kohyo No. 503148/1987 has proposed a bone cementcomprising di(meth)acrylate and inorganic filler particles which are atleast partially absorbed by the bone.

The above-mentioned bone cements are characterized by the use of abiocompatible filler, and the latter is particularly advantageous inthat it does not contain methyl methacrylate which is problematic interms of toxicity and adhesive strength. These bone cements may providefavorable results in terms of biocompatibility, whereas are notnecessarily satisfactory in terms of operability.

Speaking from the aspect of operability, quick and thorough mixing isrequired to simultaneously solve the above-mentioned problems 5 and 6which may seem inconsistent. In addition, the bone cement is required tohave an adequate flowability before curing to facilitate filling intothe affected part.

A practical bone cement should afford sufficient adhesive strengthbetween the cured material and hard tissues, and the cured materialshould have sufficient water resistance permitting retention of suitablestrength in the body for an extended period of time.

The present invention aims at providing a restorative composition forhard tissue, which is capable of exhibiting the above-mentionedproperties requested as a practical bone cement, and which is superiorin biocompatibility and operability.

The present invention also aims at providing a method for dispensingsuch restorative composition for hard tissue.

DISCLOSURE OF THE INVENTION

The present inventors have found that a restorative composition for hardtissue comprising a paste obtained by mixing, at a certain ratio, aninorganic calcium phosphate powder superior in biocompatibility andadhesion to bone, and a polymerizable monomer capable of impartingsufficient mechanical strength and water resistance to the curedmaterial meets the aforementioned objects of the present invention, andfurther studies resulted in the completion of the present invention.

Accordingly, the present invention provides a restorative compositionfor hard tissue, comprising a paste (A) containing an inorganic calciumphosphate powder (hereinafter to be briefly referred to as inorganicpowder), a polymerizable monomer mixture (hereinafter briefly referredto as monomer mixture) and a polymerization initiator, and a paste (B)containing an inorganic powder, a monomer mixture and a polymerizationaccelerator, wherein the content of the inorganic powder in each pasteis 75-85% by weight, and the above-mentioned polymerizable monomermixtures each contain a monomer of the formula (1): ##STR3## wherein R¹and R² may be the same or different and each is a hydrogen atom or amethyl, and p is an integer of 1-4, and a monomer of the formula (2):##STR4## wherein R³ and R⁴ may be the same or different and each is ahydrogen atom or a methyl, m and n are each an integer of 1-5, and m+nis 2-6, the monomer of formula (1) being contained in a proportion of40-65% by weight based on the total weight of the monomer mixtures.

The present invention also provides a method for dispensing theabove-mentioned restorative composition for hard tissue.

As used herein, the term "hard tissue" denotes hard tissues in livingorganisms, such as bones, cartilages, joints and teeth.

As used herein, "being superior in operability" means that therespective pastes (A) and (B) constituting the restorative compositionfor hard tissue have adequate flowability or consistency.

The consistency of the paste is expressed by the diameter (mm) of ashape formed by a certain amount of the paste which was interposedbetween two glass plates and applied with a certain pressure for apredetermined time. The preferable consistency of the paste when 0.5 mlof the paste is applied with a 40 g pressure at 25° C. for 30 seconds isexpressed by a diameter of not less than 20 mm and not more than 27 mm.

When the consistency of the paste falls within such range, the paste canbe mixed homogeneously, and the obtained restorative composition forhard tissue has suitable flowability which desirably permits easyapplication of the composition to the affected part. In particular, theuse of the dispenser to be mentioned later enables simultaneousoperation of the above-mentioned mixing and filling.

The flowability of the paste is quantitatively defined by the forcenecessary for extruding, at a predetermined rate, a certain amount ofpaste filled in a container having a certain shape. To be specific, thematerial is filled in a cylinder having an inner diameter of 13 mm anddelivery end diameter of 3.5 mm, and a piston placed in the cylinder ispressed thereinto at 5 mm/min at 25° C. The flowability is expressed bythe force required to press the piston deeper in. The paste having asuitable flowability preferably requires an extrusion force of not morethan 2N, more preferably not more than 1N. When the paste has aflowability falling within the above-mentioned range, the forcenecessary for the above-mentioned mixing and filling operation can besmall enough to enable performing such operation easily with one hand.

A paste having too high a flowability drips from a dispenser and flowsout from the application site, while a paste having too low aflowability is associated with difficulty in being extruded from adispenser, so that it cannot be sufficiently injected into theapplication site. Either instance is inconvenient for operation.

The inorganic powder to be used in the present invention is exemplifiedby calcium secondary phosphate, octacalcium phosphate, α-tricalciumphosphate, β-tricalcium phosphate, tetracalcium phosphate andhydroxyapatite, with preference given to α-tricalcium phosphate,β-tricalcium phosphate and hydroxyapatite in view of superiorbiocompatibility.

In the present invention, the inorganic powder content of the respectivepastes (A) and (B) should be 75-85% by weight.

When the inorganic powder content of the respective pastes is less than75% by weight, various defects are caused. For example, greater part ofthe surface of the inorganic powder is covered with polymer, so that theadhesion to bone is prevented and biocompatibility becomes poor; whenthe restorative composition for hard tissue is cured, polymerizationgenerates greater heat with the likelihood of giving damages to thepatient's tissues; and the strength of the cured material becomesinsufficient. On the other hand, when the inorganic powder content ofthe respective pastes exceeds 85% by weight, the flowability of thepaste becomes low, and in some cases, a homogeneous restorativecomposition cannot be obtained, which in turn results in failure torealize the objective superior operability of the present invention.

It is preferable that the components of the inorganic powder in paste(A) and contents thereof, and those in paste (B) be the same.

The inorganic powder to be used in the present invention preferably hasa particle size of 0.1-100 μm, more preferably 0.1-50 μm. Such widedistribution of particle size of the inorganic powder enables increaseof the inorganic powder content of the paste.

The inorganic powder is preferably compact. The term "compact" heremeans that the powder does not substantially have voids, and such powderis exemplified by those wherein the volume of fine voids as measured bythe mercury intrusion method is not more than 0.1 ml/g. When theinorganic powder having the volume of fine voids which falls within saidrange is used, a monomer mixture to be mixed with the inorganic powderis not absorbed into the voids in the inorganic powder, and arestorative composition having the above-mentioned high inorganic powdercontent can be obtained.

For a stable restorative composition to be obtained by mixing aninorganic calcium phosphate powder and an organic monomer mixture, it ispreferable to introduce an organic group onto the surface of theinorganic powder. For this end, a treatment with an organic silanecoupling agent may be performed. Specifically, an inorganic powder issubjected to a primary treatment with an organic silane coupling agent,a heat-treatment, and then a secondary treatment with an organic silanecoupling agent, whereby a restorative composition having a suitableflowability can be obtained and the strength of the cured material canbe improved. This is considered to be attributable to the treatment withan organic silane coupling agent and heat treatment applied to thesilicon-free inorganic calcium phosphate powder, thereby introducingsilicon onto the surface of the inorganic powder, which silicon is thenbound with the second organic silane molecule.

The organic silane coupling agent is exemplified byγ-methacryloxypropyltrimethoxysilane,γ-methacryloxypropyltriethoxysilane,γ-methacryloxypropyl-tris(β-methoxyethoxy)silane andγ-aminopropyltriethoxysilane. While the silane coupling agent to be usedfor the two organic silane treatments may be the same or different, asilane coupling agent having polymerizable double bond, such asγ-methacryloxypropyltrimethoxysilane, is preferably used for the secondtreatment to provide stronger bond with the cured material. The heattreatment to be performed in between the two silane treatments may beperformed at a temperature at which the organic silane coupling agentintroduced by the first silane treatment can be thermally decomposed.Inasmuch as a high temperature may affect the composition and structureof the inorganic powder, the desirable temperature of the heat treatmentis 300° C.-800° C.

The monomer mixture to be used in the present invention contains amonomer of the formula (1): ##STR5## wherein R¹ and R² may be the sameor different and each is a hydrogen atom or a methyl, and p is aninteger of 1-4, and a monomer of the formula (2): ##STR6## wherein R³and R⁴ may be the same or different and each is a hydrogen atom or amethyl, m and n are each an integer of 1-5, and m+n is 2-6.

The monomer of the formula (1) is a highly flowable liquid and isrequired for dissolving other monomers and for forming a stablerestorative composition by homogeneously mixing with an inorganicpowder. This monomer is hydrophilic and remains in a trace amount on thesurface of the cured material due to the polymerization inhibitoryaction of the surrounding oxygen. This residual monomer is considered todissolve in surrounding water, whereby particles of inorganic powderhaving affinity for hard tissue come into direct contact with thesurrounding hard tissue, and bind therewith to strengthen the adhesionto the hard tissue.

FIG. 1 is a surface scanning electron microphotograph of a plate-shapedcured material formed from the restorative composition (composition ofExample 1 to be described later) of the present invention. As is evidentfrom this photograph, the surface of the cured material formed from therestorative composition of the present invention exposes inorganicparticles. In contrast, FIG. 2 is a surface scanning electronmicrophotograph of a cured material obtained from the composition(composition of Comparative Example 3 to be described later) disclosedin EP-B-123323. This composition does not comprise a monomer of theformula (1) which is an essential element in the present invention.Therefore, the inorganic particles on the surface of the cured materialare covered with polymer, and cannot directly adhere to the hard tissuein the body. In consequence, such composition is considered to beinferior to the composition of the present invention in the adhesion ofthe cured material to the hard tissue.

Examples of the monomer (1) of the formula (1) include ethyleneglycoldimethacrylate, diethyleneglycol dimethacrylate, triethyleneglycoldimethacrylate and propyleneglycol dimethacrylate, with preference givento triethyleneglycol dimethacrylate.

The monomer of the formula (2) is a liquid having low flowability and isrequired for retaining the inorganic powder to form a stable restorativecomposition. This monomer is hydrophobic and is also required forimproving the water resistance of the cured material.

Examples of the monomer (2) include2,2-bis(4-methacryloxyethoxyphenyl)propane,2,2-bis(4-methacryloxypolyethoxyphenyl)propane,2,2-bis(4-methacryloxypolypropoxyphenyl)propane, with preference givento 2,2-bis(4-methacryloxyethoxyphenyl)propane.

It is the composition of the monomer mixture that is important in thepresent invention to achieve superior operability. That is, the contentof the monomer of the formula (1) should be 40-65% by weight, preferably45-60% by weight, of the total weight of the monomer mixtures. When thecontent of the monomer of the formula (1) is beyond 65% by weight of thetotal weight of the monomer mixtures, the obtained paste shows poorstability, allowing separation of the inorganic powder from the paste.On the other hand, when the content of the monomer of the formula (1) isless than 40% by weight of the total weight of the monomer mixtures, theflowability of the paste becomes too low to realize the objectivesuperior operability of the present invention.

The monomer of the formula (2) is added such that the total of themonomer of the formula (1) and that of the formula (2) and the thirdcomponent to be described later becomes 100% by weight.

The above-mentioned monomer mixture may contain a third component suchas hydrophobic dimethacrylate (e.g.,2,2-bis(4-(3-methacryloxy-2-hydroxypropoxy)phenyl)propane (hereinafterabbreviated as Bis-GMA) and 2,2-bis(4-methacryloxyphenyl)propane). Thehydrophobicity here means that the saturation solubility inphysiological saline at 37° C. is not more than 500 ppm.

Such hydrophobic dimethacrylate is used in an amount corresponding to0-30% by weight of the total monomer mixtures.

The monomer mixture constituting paste (A) and the monomer mixtureconstituting paste (B) preferably have the same composition.

The polymerization initiator or polymerization accelerator to be used inthe present invention when added alone does not initiate polymerizationat normal temperature in a short time. By mixing them, however, radicalsare produced which function to cure the monomer mixture.

Examples of the polymerization initiator include organic peroxides suchas diacyl peroxides and peroxy esters. Specific examples thereof includebenzoyl peroxide, 2,4-dichlorobenzoyl peroxide, m-tolyl peroxide,t-butyl peroxybenzoate, di-t-butyl peroxyisophthalate,2,5-dimethyl-2,5-di(benzoylperoxy)hexane,2,5-dimethyl-2,5-di((o-benzoyl)-benzoylperoxy)hexane and2,5-dimethyl-2,5-di((o-benzoyl)-benzoylperoxy)hexine-3,3,3',4,4'-tetra(t-butylperoxycarbonyl)benzophenone.

The polymerization accelerator is preferably a tertiary amine havingamino group directly bonded to the aromatic ring, which is exemplifiedby N, N-dimethyl-p-toluidine, N,N-dimethylaniline,N-methyl-N-(2-hydroxyethyl)aniline, N,N-di(2-hydroxyethyl)aniline,N,N-di(2-hydroxyethyl)-p-toluidine, N,N-di(2-hydroxypropyl)aniline andN,N-di(2-hydroxypropyl)-p-toluidine.

These polymerization initiator and polymerization accelerator need to beused in an amount enough to sufficiently cure the monomer mixture, whichis generally 0.1-2% by weight relative to the monomer mixture, for theboth.

When the both pastes are mixed in the present invention, the surface ofthe mixture is sometimes slow in curing due to the oxygen in the air. Toprevent this, a light polymerization initiator may be further added tothe paste, by which curing may be effected also from the surface uponirradiation of the light, which is particularly effective in the case ofa bone cement for fixing artificial joints in that the fixing takes onlya short time. Such light polymerization initiator may be a combinationof camphor quinone and amines.

The restorative composition for hard tissue of the present invention ispreferably sterilized, which may be achieved by separately sterilizingthe monomer mixture and inorganic powder, and mixing them to give apaste. Alternatively, sterilization may be applied after forming thepaste. The method for sterilization can be appropriately selected fromknown methods such as EOG sterilization and filtration.

While the mixing ratio of paste (A) and paste (B) is not particularlylimited, it is preferably 1:10-10:1, most preferably 1:1 by volume.

The restorative composition for hard tissue of the present inventionsuffers from insufficient strength of the cured material unless paste(A) containing a polymerization initiator and paste (B) containing apolymerization accelerator are homogeneously mixed, whereas excess timefor mixing leads to the initiation of curing before application of themixture to the affected part, thereby making the mixture unavailable. Inaddition, air foams mixed therein could cause insufficient strength.Contamination of bacteria in the air during mixing and volatilization ofthe monomer vapor into the air should be prevented. The both pastesshould be preserved in separate containers, since curing starts uponmixing, and are preferably mixed with ease when in use. Consequently, asupply apparatus comprising two containers to place both pastes inseparately, extrusion mechanisms to deliver the pastes from the twocontainers, delivery holes in said containers, and a static mixermechanism to lead and homogeneously mix the both pastes delivered fromsaid delivery holes is most suitably used for the object of the presentinvention.

A preferable method is the use of a static mixer described in aliterature S. D. Cheng et al., Static Mixing Handbook-Everything aboutStatic Mixing Process, Sogo Kagaku Kenkyusho, pp. 9-15 (1973)!. The useof this apparatus enables homogeneous mixing of the two pastes (A) and(B), and sterile application of the obtained composition to the affectedpart in an efficient manner in a short time.

When the restorative composition for hard tissue is applied to theaffected part using this static mixer, too low a flowability of thepaste makes it difficult for the mixer to deliver the paste, and toohigh a flowability causes dripping of the paste from the tip of themixer and defective shape-forming performance of the paste. Thus, thedispensing method of the present invention is characterized by thecombination of a paste composition which affords appropriate consistencyand a supply apparatus for homogeneously mixing the paste and injectingthe paste composition into the affected part.

FIG. 3 shows one example of the apparatus to be used for mixing thepastes. The apparatus consists of a dispenser 1, a mixer 2, a pair ofsyringe 3 containing paste (A) and syringe 3' containing paste (B), anda plunger 4. When the trigger of the dispenser 1 is pulled, the plunger4 is pressed deeper in and each paste in the syringes 3 and 3' isextruded through a common delivery hole 5 into the mixer 2. The mixer 2has baffles to continuously perform separation and mixing. The pastesare thoroughly mixed while being carried through the mixer 2 andinjected into the affected part directly from the outlet of the mixer 2or via a tube having a desired length.

In view of the use of the apparatus upon direct contact with the tissueswithin the body of patients, it is desirable that the apparatus besterilized. The method for sterilization can be appropriately selectedfrom known methods such as EOG sterilization and autoclavesterilization. The mixer 2 and syringes 3 and 3' are desirablydisposable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a surface electron microphotograph of a plate-shaped curedmaterial obtained from the composition of Example 1.

FIG. 2 is a surface electron microphotograph of a plate-shaped curedmaterial obtained from the composition of Comparative Example 3.

FIG. 3 is a schematic view (lengthwise cross section) of the apparatusto be used for mixing the pastes, wherein 1 is a dispenser, 2 is amixer, 3 and 3' are syringes, and 4 is a plunger.

The present invention is explained in the following by way of Examples,to which the present invention is not limited.

Reference Example 1 (production of hydroxyapatite powder)

According to the method described in the literature E. Hayek and H.Newesel, "Inorganic Synthesis VII", McGraw-Hill, p. 63, New York(1963)!, an aqueous solution of ammonium hydrogenphosphate, an aqueoussolution of calcium nitrate and aqueous ammonia were mixed in a Ca/PO₄molar ratio of 1.67 and heated to synthesize hydroxyapatite. Thehydroxyapatite obtained was subjected to centrifugal dehydration, driedat 80° C., sintered at 1100° C. for 2 hours, and pulverized in a ballmill to give a hydroxyapatite powder having an average particle size of4 μm, particle size 0.1-50 μm, density 3.27 g/ml and pore volume 0.057ml/g.

The obtained hydroxyapatite powder (400 g) was added to a solution (240ml) of γ-methacryloxypropyl trimethoxysilane (8 g) in acetone, and themixture was stirred at room temperature for one hour. Acetone wasdistilled away under reduced pressure, and the residue was dried at roomtemperature and heated at 750° C. for 2 hours. Then, the obtained powderwas added to a solution (600 ml) of γ-methacryloxypropyltrimethoxysilane (8 g) in toluene, which was followed by refluxing underheating for 3 hours. Toluene was distilled away under reduced pressure,and the residue was dried at room temperature.

Reference Example 2 (determination of the composition of polymerizablemonomer mixture)

Triethylene glycol dimethacrylate (hereinafter to be abbreviated asTEGDMA) as the monomer of the formula (1),2,2-bis(4-methacryloxyethoxyphenyl)propane (hereinafter to beabbreviated as Bis-MEPP) as the monomer of the formula (2), and Bis-GMAas the third component dimethacrylate were mixed in the weight ratioshown in Table 1, and benzoyl peroxide (0.3 part by weight) andhydroxyapatite powder (80 parts by weight) obtained in Reference Example1 were added to this monomer mixture (20 parts by weight), which mixturewas well admixed in a mortar to give a paste. The obtained paste wasfilled in a cylinder (inner diameter 13 mm, delivery end diameter 3.5mm). The force necessary for pressing the piston placed in the cylinderthereinto at 5 mm/min was measured using Instron universal testingmachine, the results of which are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    monomer                                                                       composition                                                                          1  2  3  4  5  6  7  8  9  10 11                                       __________________________________________________________________________    TEGDMA*                                                                              30 40 50 50 50 50 50 70 70 70 100                                      Bis-MEPP*                                                                            35 30 50 40 30 20  0 30 15  0 0                                        Bis-GMA*                                                                             35 30  0 10 20 30 50  0 15 30 0                                        force (N) nec-                                                                       3.14                                                                             1.08                                                                             1.67                                                                             1.37                                                                             1.08                                                                             0.39                                                                             0.59                                                                             -- -- -- --                                       cesary for                                                                    extrusion                                                                     __________________________________________________________________________     *parts by weight                                                         

In Table 1, "-" means sedimentation of hydroxyapatite powder. When thecontent of TEGDMA in the monomer mixture was not more than 25% byweight, the monomer mixture had low flowability, which in turn resultedin failure to homogeneously admix the monomer mixture and thehydroxyapatite powder.

As a result, it has been found that the TEGDMA content of the monomermixture as a whole should be 40-65% by weight to afford arestorativecomposition for hard tissue, which has a superior operabilityrequesting an extrusion force of not more than 2N.

EXAMPLE 1

(Preparation of paste)

TEGDMA (50 parts by weight), Bis-MEPP (20 parts by weight) and Bis-GMA(30 parts by weight) were mixed, and benzoyl peroxide (0.3 part byweight) and hydroxyapatite powder (80 parts by weight) obtained inReference Example 1 were added to this monomer mixture (20 parts byweight), which mixture was well admixed in a mortar to give a paste(A1). Separately, a monomer mixture (20 parts by weight) same as abovewas admixed with N,N-di(2-hydroxypropyl)-p-toluidine (0.4 part byweight) and hydroxyapatite powder (80 parts by weight) to give a paste(B1).

(Evaluation of the water resistance of cured material)

Equivalent amounts of the paste (A1) and paste (B1) obtained in theabove were mixed in a dispenser shown in FIG. 3. The obtainedcomposition was extruded in a Teflon tube and allowed to cure to give around rod cured material having a diameter of 3 mm and a length of 25mm.

The obtained cured material was immersed in physiological saline at 37°C. and preserved for a certain time. The cured material was weighedbefore and after the preservation, based on which water absorption wascalculated.

The flexural strength of the cured material was determined in the air atroom temperature by the three-point support method (distance betweenleading points 20 mm, head speed 1 mm/min) by Instron strength testingmachine. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Water absorption                                                                            1 week later       0.08                                         (%)           2 weeks later      0.14                                         Flexural strength                                                                           immediately after preparation                                                                    114.3                                        (MPa)         1 week later       116.3                                                      2 weeks later      120.2                                        ______________________________________                                    

As is shown in Table 2, water absorption of the cured material wasextremely small, and the mechanical strength of the cured material wasretained even after immersion in physiological saline, whereby it hasbeen clarified that the cured material has superior water resistance.

(Determination of heat generated during curing)

A chromel-almel thermocouple was fixed on the outside of 2.8 ml glasssample bottle. Equivalent amounts of the obtained paste (A1) and paste(B1) were placed in the sample bottle and mixed, and the maximumtemperature reached by the heat generated during curing was measured.

As a result, the temperature reached 46° C. in 4.9 minutes from theinitiation of the mixing.

(Effect of monomer (1))

Equivalent amounts of the obtained paste (A1) and paste (B1) were mixed.The obtained composition was interposed between two Teflon sheets andallowed to polymerize at room temperature for 10 minutes to give aplate-shaped cured material, which was immediately washed with water toremove the uncured layer on the surface.

Gold was deposited on the obtained plate-shaped cured material and thesurface was observed in a scanning electron microscope. The results areshown in FIG. 1.

As is evident from FIG. 1, a number of hydroxyapatite particles(portions that look white in the photograph) were found on the surfaceof the obtained cured material.

(Effect of surface treatment of inorganic particles)

Equivalent amounts of the obtained paste (A1) and paste (B1) were mixed,and the mixture was allowed to cure to give a round rod having adiameter of 3 mm and a length of 28 mm, and a round rod having adiameter of 4 mm and a length of 4 mm.

The flexural strength of the former test sample was determined (thethree-point support method, distance between leading points 20 mm, headspeed 1 mm/min) by Instron strength testing machine, and the compressivestrength of the latter test sample was determined (head speed 2 mm/min)by Instron strength testing machine in the air at room temperature(number of samples: 10, respectively).

The results revealed that the flexural strength was 118.1±10.6 MPa andthe compressive strength was 239±13 MPa.

Comparative Example 1

Using commercially-available polymethyl methacrylate bone cement(polymerizable monomer content of the entire composition; 33% byweight), the temperature of the heat generated by curing was measured inthe same manner as in Example 1.

As a result, the temperature reached 76.3° C. in 7.7 minutes from theinitiation of the mixing of the powder agent and the liquid agent.

EXAMPLE 2

(Preparation of paste)

TEGDMA (50 parts by weight), Bis-MEPP (20 parts by weight) and Bis-GMA(30 parts by weight) were mixed, and benzoyl peroxide (0.3 part byweight) and hydroxyapatite powder (75 parts by weight) obtained inReference Example 1 were added to this monomer mixture (25 parts byweight), which mixture was well admixed in a mortar to give a paste(A2). Separately, a monomer mixture (25 parts by weight) same as abovewas admixed with N,N-di(2-hydroxyethyl)-p-toluidine (0.5 part by weight)and hydroxyapatite powder (75 parts by weight) to give a paste (B2).

(Effect of inorganic powder content)

Equivalent amounts of the paste (A2) and paste (B2) were mixed, andplaced in a brass mold to allow curing at room temperature. The mixturewas allowed to stand overnight at 37° C. to give a round rod having adiameter of 4 mm and a thickness of 4 mm.

The obtained round rod was immersed in water at 70° C. for 24 hours, andwater absorption was calculated from the weight thereof before and afterthe immersion. In the same manner as in Example 1, compressive strengthin the air after immersion in water was determined (number of samples:10).

The results are shown in Table 3.

Comparative Example 2

According to Japanese Patent Application under PCT laid-open under KohyoNo. 503148/1987, TEGDMA (50 parts by weight) and Bis-GMA (50 parts byweight) were mixed, and benzoyl peroxide (1 part by weight) andhydroxyapatite powder (70 parts by weight) were added to this monomermixture (30 parts by weight), which mixture was well admixed in a mortarto give a paste (C). Separately, a monomer mixture (30 parts by weight)same as above was admixed with N,N-di(2-hydroxyethyl)-p-toluidine (0.6part by weight) and hydroxyapatite powder (70 parts by weight) to give apaste (D).

Equivalent amounts of the paste (C) and paste (D) were mixed. In thesame manner as in Example 2, round column specimens were prepared, andwater absorption and compressive strength in the air after waterabsorption were determined (number of samples: 10).

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                           Compressive strength after                                          Water absorption                                                                        water absorption                                           ______________________________________                                        Example 2  0.28 ± 0.09%                                                                           178 ± 12 MPa                                        Comparative                                                                              0.69 ± 0.21%                                                                           155 ± 11 MPa                                        Example 2                                                                     ______________________________________                                    

Table 3 shows significant difference of significance level of not morethan 1% between Example 2 and Comparative Example 2 in water absorptionand compressive strength after water absorption by the t-test.

Comparative Example 3

According to EP-B-123323, only Bis-MEPP was used as a monomer. Benzoylperoxide (0.3 part by weight) and hydroxyapatite powder (80 parts byweight) were added to the monomer (20 parts by weight), which mixturewas well admixed in a mortar to give a paste (E). Separately, a monomer(20 parts by weight) same as above was admixed withN,N-di(2-hydroxyethyl)-p-toluidine (0.5 part by weight) andhydroxyapatite powder (80 parts by weight) to give a paste (F).

Equivalent amounts of the paste (E) and paste (F) were admixed and aplate-shaped cured material was prepared in the same manner as inExample 1 (Effect of monomer (1)), and a surface electronmicrophotograph thereof was taken (FIG. 2). As is evident from FIG. 2,the cured material obtained from the composition of Comparative Example3 without monomer (1) had a polymer membrane formed from a monomer onthe hydroxyapatite particles.

Comparative Example 4

According to U.S. Pat. No. 4778834, hydroxyapatite (10 g) was stirred inan aqueous solution of sodium methasilicate 9 hydrate (0.5 g/70 ml,adjusted to pH 6.8 with 1N HCl) at room temperature overnight, washed,dried, and refluxed under heating for 3 hours in a solution (0.2 g/15ml) of γ-methacryloxypropyl trimethoxysilane in toluene to givehydroxyapatite particles. In the same manner as in Example 1 except thatthe hydroxyapatite particles thus obtained were used, paste (G) andpaste (H) were obtained.

Equivalent amounts of the obtained paste (G) and paste (H) were mixedand cured, and the flexural strength and compressive strength of thetest samples were determined in the same manner as in Example 1 (Effectof surface treatment of inorganic particles) (number of samples: 10).

The results are shown in Table 4. The results of Example 1 are alsoshown for reference.

                  TABLE 4                                                         ______________________________________                                                  Flexural strength                                                                         Compressive strength                                    ______________________________________                                        Example 1   118.1 ± 10.6 MPa                                                                         239 ± 13 MPa                                     Comparative 89.6 ± 6.2 MPa                                                                           210 ± 8 MPa                                      Example 4                                                                     ______________________________________                                    

There was found significant difference of significance level of not morethan 1% between Example 4 and Comparative Example 3 in flexural strengthand compressive strength by the t-test.

The consistency of the pastes of Example 1 and Comparative Example 4 wasmeasured. That is, a glass plate weighing 40 g was placed on 0.5 ml ofeach paste, and the diameter of the paste was measured 30 seconds later.The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                       Consistency (mm)                                               ______________________________________                                        Example 1                                                                     paste (A1)       23.5                                                         paste (B1)       26.0                                                         Comparative Example 4                                                         paste (G)        17.3                                                         paste (H)        19.0                                                         ______________________________________                                    

It has been recognized that the paste (A1) and paste (B1) of Example 1are able to provide a restorative composition for hard tissue, which hasa flowability suitable for extrusion from a dispenser.

Industrial Applicability

The restorative composition for hard tissue of the present inventionshows high adhesion to bones and has sufficient water resistance. Theheat generated by curing is small and gives minimal damage to thetissues of patients. In addition, the paste constituting the restorativecomposition for hard tissue has an adequate consistency, whichfacilitates homogeneous mixing of the pastes and application of thethereby-obtained mixture to the affected part by the use of a dispensingapparatus.

Therefore, the restorative composition for hard tissue of the presentinvention can be effectively used not only as a bone cement but also asa filler for the missing part of the bone, a bone prosthesis or anartificial bone.

What is claimed is:
 1. A restorative composition for hard tissue,comprising a paste (A) comprising an inorganic calcium phosphate powder,a polymerizable monomer mixture and a polymerization initiator, and apaste (B) comprising an inorganic calcium phosphate powder, apolymerizable monomer mixture and a polymerization accelerator, whereinthe content of the inorganic calcium phosphate powder in each paste is75-85% by weight, and the above-mentioned polymerizable monomer mixtureseach contain a monomer of the formula (I): ##STR7## wherein R¹ and R²may be the same or different and each is a hydrogen atom or a methyl,and p is an integer of 1-4, and a monomer of the formula (2): ##STR8##wherein R³ and R⁴ may be the same or different and each is a hydrogenatom or a methyl, m and n are each an integer of 1-5, and m+n is 2-6,the monomer of formula (1) being contained in a proportion of 40-65% byweight based on the total weight of the monomer mixtures wherein saidpaste (A) and said paste (B) each have a consistency in the range 20-27mm and wherein the inorganic calcium phosphate powder has been subjectedto primary treatment with an organic silane coupling agent, heat-treatedat a temperature of 300°-800° C. and subjected to secondary treatmentwith an organic silane coupling agent.
 2. The restorative compositionfor hard tissue of claim 1, wherein the monomer of the formula (1) istriethylene glycol dimethacrylate and the monomer of the formula (2) is2,2-bis(4-methacryloxyethoxyphenyl)-propane.
 3. A method for filling acavity of hard tissue comprising placing separately the paste (A) andthe paste (B) as defined in claim 1 into two containers of a dispensingapparatus, mixing homogeneously said two pastes by a static mixermechanism of the dispensing apparatus and extruding the mixed paste tothe cavity of hard tissue from the dispensing apparatus.